A cytoplasmic pattern of p53 immunohistochemical expression has recently been reported in a rare subset of pelvic and endometrial cancers with a TP53 mutation involving domains affecting nuclear localization. This study reports the clinicopathologic features of 31 cases with a TP53 mutation involving nuclear localization, the largest study to date, emphasizing practical strategies for recognizing this uncommon variant and distinguishing it from the p53 wild-type pattern. The study also evaluates the prognostic significance of TP53 mutation involving nuclear localization in the ovarian high-grade serous carcinoma (HGSC) cohort of The Cancer Genome Atlas database. Most of the 31 tumors were advanced stage pelvic or endometrial HGSC. All TP53 mutations were predicted to result in loss of function. The p53 overexpression pattern was present in 6 tumors; the p53 null pattern in 3 and the p53 cytoplasmic pattern in 22 tumors. The p53 cytoplasmic pattern predominantly consisted of weak to moderate cytoplasmic staining in >95% of tumor cells as well as variable intensity nuclear staining involving a range of just a few cells to just under 80% of tumor cells. The p53 cytoplasmic pattern was observed in 100% of tumors with TP53 mutation in the nuclear localization domain and in 33% to 44% of tumors with a mutation in the adjacent tetramerization domain or nuclear exclusion sequence (P<0.01). p16 immunoexpression was present in 74% of tumors. In The Cancer Genome Atlas ovarian HGSC cohort, 9% of 471 nonredundant TP53-mutant cases had a nuclear localization domain, tetramerization domain, or nuclear exclusion sequence mutation but there was no significant difference in survival when compared to cases with TP53 mutation outside those domains (P>0.05). p53 cytoplasmic staining merits classification as an aberrant result despite coexisting nuclear staining that in some cases may resemble the p53 wild-type pattern. While positive p16 immunostaining may be of value to confirm diagnostically challenging cases of p53 cytoplasmic staining, a negative result is noninformative and molecular testing for TP53 mutation should be considered, if available.
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